NO122009B - - Google Patents

Description

Process for the production of new organic N-oxides.

The object of the present invention is a method for the production of new organic N-oxides, and which is

characterized by treating compounds whose nucleus has the formula

which in positions 3, 15 and 20 have the stereochemical configuration of reserpine and at least one substituent in the ring E, with N-oxidizing agents. We could thereby determine that the new compounds obtained in this way produce N-oxides of the starting material and thus have the grouping As starting material, the entire range of compounds that exhibit the nucleus shown above can be used, and in particular those that in at least the positions 16 , 17 or 18 has a substituent, such as a free, esterified or etherified hydroxyl group, a free or esterified carboxyl group or a free or functional derivative, e.g. catalyzed keto group. These compounds may also contain additional substituents, such as in ring A, e.g. in the 11-position a lower alkoxy, such as a methoxy group. Preferably, compounds with the formula are used

wherein R means hydrogen or a methoxy group, R 2 means a hydroxyl group and Rx means a free or esterified carboxyl group, or R 2 means an esterified hydroxyl group and Rx an esterified carboxyl group. As such, mention should be made of reseric acid and its esters with alcohols, such as methanol, ethanol, propanol or butanol, reserpsyrelactone, the corresponding compounds of the deserpidine series, esters from reseric acid, in which both the oxy group and the carboxyl group are esterified, such as reserpine, rescinnamine , lower alkyl reserpate esters with acids, such as sulphonic acids, e.g. p-toluenesulfonic acid, preferably carboxylic acids, such as aliphatic, especially substituted or substituted lower alkane carboxylic acids, e.g. acetic acid, propionic acid, succinic acid or haloacetic acids, aromatic carboxylic acids, primarily benzoic acids, p-chloro-, p-methyl, p-acetyl-amino-benzoic acid, salicylic acid, 3,4-dihydroxy-, 3,5-dihydroxy- , 2-methyl-4,6-dihydroxy-, 2,3,4-trihydroxy-benzoic acid, benzoic acids containing at least one alkoxy group, such as 4-methoxy, 3,4-di-methoxy-, 3,4- methylenedioxy-, 3,4,5-trietoxy- or 3,4,5-trimethoxy-benzoic acids, syringa, 0,-carboethoxy- or -propoxy-syringa, vanillic or isovanillic acid, ar-aliphatic carboxylic acids, such as mandel -, tropa-, cinnamic or 3,4,5-trimethoxy-cinnamic acids or monocyclic, heterocyclic carboxylic acids, such as furanic, thiophene-, pyrrole- or pyridine-carboxylic acids, e.g. f uran-(2)-carboxylic acid, thiophene-(2)-carboxylic acid, nicotinic, isonicotinic or quinoline carboxylic acids, or the corresponding diesters of the deserpidic acid series, such as deserpidine. 18-halogeno-deoxy-reserpic acid and its esters, reserpinol, deserpidinol, reserpindiol or deserpidindiol and its esters, 3-epi-alloyohimbone, 3-epi-α-yohimbic acid and its esters and alkyl-anhydro-reserpates can also be used as starting materials.

The starting materials are known or can

are produced according to procedures known per se. Thus, reser acid and its mono- and diesters can be produced, e.g. according to the method described in Norwegian patent no. 87,348, deserpidic acid and its mono- and diesters according to patent no. 91,946.

The method according to the present invention can be carried out with N-oxidizing agents, such as hydrogen peroxide or ozone. However, it is advantageous to use inorganic or organic peracids, such as monopersulfuric acid, p-toluene-persulphonic acid, primarily organic percarboxylic acids, such as peracetic acid, monoperphthalic acid and, in particular, perbenzoic acids, such as perbenzoic acid itself. The oxidation can be carried out in the absence or preferably in the presence of solvents, such as benzene, toluene, ethylene chloride, methylene chloride, chloroform, acetate and the like. Thereby, the starting materials can be used as free bases or as salts. In order to prevent oxidation of the core in the compound, elevated reaction temperatures and an excess of oxidizing agents are preferably avoided.

Depending on the working method, the new N-oxides are obtained in free form or as salts. From the free connections let in the usual way, e.g. by adding acids, salts are produced. From the salts you get, e.g. by treatment with alkali, the free bases. If the compounds obtained contain free carboxylic acids, it is also possible to prepare salts with metals, such as alkali or alkaline earth metals.

The N-oxides thus obtained can further be subjected to such reactions that can convert the functional groups in ring E. Thus, compounds with esterified hydroxyl and/or carboxyl groups in ring E, such as reser acid or deserpidic acid mono- and -diester- N-oxides can be treated with alkaline saponifying agents and those with free oxy and/or carboxyl groups with esterifying agents. Depending on the way of working, it is therefore possible, e.g. to cleave both ester groups or only to saponify the esterified hydroxyl group. To achieve one purpose or another, one can work with different stronger or weaker alkaline saponifying agents, or with the same under different strong conditions, such as in the presence or absence of water, at lower or higher temperatures or for longer or shorter periods of time. Thus, both ester groups allow themselves to be hydrolysed by prolonged heating of diester N-oxides with the solution of an alkali hydroxide, such as potassium hydroxide, in an alcohol, such as methanol. Treated with the same agent under milder conditions, e.g. only a short time of heating, only the esterified oxy-group is split. For partial saponification, an alkaline, saponifying agent, in particular, is allowed to act which of an esterified hydroxyl group causes the hydroxyl group to form an ester, e.g. by means of alcoholysis, in freedom, as depending on the conditions used, a conversion of the carbyloxy group takes place. Thus, one preferably works in anhydrous alcohols in the presence of alcoholates, such as alkali metal or aluminum alcoholates or other alcoholizing agents, such as sodium carbonate or piperidine. In absolute methanol, in the presence of e.g. an alkali metal methylate, such as sodium methylate or aluminum tertiary butylate, piperidine or sodium carbonate, the methyl ester is formed. If the alcoholysis is carried out in other absolute alcohols, such as ethanol or butanol, in the presence of corresponding alcoholates, such as e.g. sodium ethylate or -butylate or other alcoholyzing agents, the corresponding ethyl or butyl ester N-oxides are obtained. Ester N-oxides can be converted to the corresponding acid N-oxides by further treatment in a stronger alkaline saponifying medium.

N-oxides with esterified carboxyl groups can also be obtained when one transfers an acid N-oxide directly or via its functional derivatives to the ester with an alcohol. In addition, the acid N-oxide or one of its salts can be treated with such esterifying agents, which manage to transfer a carboxyl group to an esterified carboxyl group. Preferably, an acid N-oxide is reacted with diazoalkanes, such as diazomethane, or esterified with alcohols, especially alkanols, e.g. in the presence of stronger acids, such as the hydrohalic acids.

Compounds according to the invention can serve as intermediates for production

of medicines. They already partially show themselves

sedative effect and can be used as medicines. Thus, the N-oxides in particular are off

the diester of reserpic acid and deserpidic acid

sedative and can be used as

medicine for the treatment of nervous conditions. A particular advantage of these N-oxides compared to the corresponding tertiary ones

amines is their increased solubility in polar solvents, such as alcohols.

The invention also includes such modifications of the method, where one

assumes a connection that can be made

any step of the process as intermediates, and performs the still missing process steps.

The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.

Example 1:

640 mg of deserpidine dissolved in 30 cm'<1 >methylene chloride is added dropwise at 0° 3.62 cm<3> a 0.61-n. solution of perbenzoic acid in chioroform. After 15 minutes, the reaction mixture is washed with dilute ammonia, then with water, dried over sodium sulfate and evaporated to dryness. The residue crystallizes from a mixture of methylene chloride and moist acetic acid ethyl ester and thus obtains deserpidine-N-oxide with m.p. 215-217° (decomposition).

By adding hydrochloric acid to a methanolic solution of deserpidine-N-oxide, the crystalline deserpidine-N-oxide hydrochloride is obtained. In a similar way, the corresponding sulphate, nitrate, perchlorate or phosphate can be obtained.

Example 2:

Dissolve 204 mg of methyl O-(3',4',5'-trimethoxy-cinnamoyl)-deserpidate in 50 cm<3> of methylene chloride and add 1.1 cm3 dropwise

of a 0.61-n. solution of perbenzoic acid in methylene chloride at 0°. It is allowed to stand for 15 minutes, the solution is washed with dilute aqueous ammonia, then with water, dried over sodium sulfate and evaporated to dryness. -cinnamoyl)-deserpidate-N-oxide, which melts at 214-216°.

In an analogous way, starting from methyl 0-(3',4'-dimethoxy-benzoyl)-deserpidate, methyl 0-(3',4'-dimethoxy-benzoyl)-deserpidate-N-oxide is obtained,

m.p. 212—213° (decomposition),

of methyl-O-furoyl-(2')-deserpidate methyl-O-furoyl-(2')-deserpidate-N-oxide, m.p. 218—220° (decomposition),

of reserpine reserpine-N-oxide, m.p. 218—

220° (decomposition),

of rescinnamine rescinnamine-N-oxide,

m.p. 217° (decomposition),

of methyl-O-acetyl-reserpate methyl-O-acetyl-reserpate-N-oxide, m.p. 258° (decomposition),

of methyl-O-(O'-carbopropoxy-syringoyl)-reserpate

methyl-O-(O'-carbopropoxy-syringoyl)-reserpate-N-oxide,

m.p. 208—209° (decomposition),

of methyl-O-nicotinoyl-reserpate methyl-O-nicotinoyl-reserpate-N-oxide, m.p. 206—208° (decomposition).

Example 3:

:. 89 mg of methyl-0-acetyl-deserpidate, dissolved in 10 cm<3> of methylene chloride, is treated dropwise with 0.676 cm3 of a 0.615-n. solution of perbenzoic acid in chloroform at 0° and working up the reaction mixture in the manner described in example 2. You thus get methyl-O-acetyl-deserpidate-N-oxide with m.p. 220° (decomp.).

Example 4:

47 mg of n-butyl-acetyl-deserpidate, dissolved in 20 ems of methylene chloride, is added to 0.212 cm<3> of a 0.945-n. solution of perbenzoic acid in methylene chloride, wash the reaction mixture with dilute ammonia, then with water and dry over sodium sulfate. The solution is evaporated to dryness and the residue, n-butyl-O-acetyl-deserpidate-N-oxide, is taken up in methanol. By adding hydrochloric acid, you get the crystalline hydrochloride of n-butyl-O-acetyl-deserpidate-N-oxide with m.p. 235—236° (decomposition).

Used instead of hydrochloric acid

sulfuric acid, nitric acid, perchloric acid or phosphoric acid, the corresponding sulfuric acid, nitric acid, perchloric acid or phosphoric acid salts are obtained.

In an analogous way, starting from methyl-O-nicotinoyl-deserpidate, methyl-O-nicotinoyl-deserpidate-N-oxide, m.p. 208—209° (decomp.),

and of n-butyl-O-acetyl-reserpate n-butyl-O-acetyl-reserpate-N-oxide, m.p. 225—227° (decomp.).

Example 5:

A solution of 6.5 g of reserpine in 200 cm<3> of methylene chloride is added dropwise to 24.2 cm<3> of a 0.892-n. solution of mono-perphthalic acid in chloroform at —5°. The reaction solution is extracted with dilute ammonia, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from moist ethyl acetate, and the reserpine N-oxide thus obtained is further purified by means of chromatography over active alumina. It melts at 218-220° (decomposition).

Example 6:

22.8 cm3 of a 0.03-n. solution of ozone in acetic acid ethyl ester is added to a solution of 204 mg of reserpine in 50 cm<3> of chloroform. The mixture is allowed to stand for 2 hours in an ice bath, the formed crystals are filtered off, dissolved in a mixture of methylene chloride and methanol and shaken vigorously with dilute ammonia. It is then washed with water and dried over sodium sulphate. The resulting solution is evaporated to dryness, and the reserpine N-oxide formed is recrystallized from a mixture of methylene chloride and moist ethyl acetate. Temp. 218— 220° C (decomposition).

Example 7:

0.20 g of reserpine N-oxide, dissolved in 5 cm<3> of methanol, is added to 0.4 g of potassium hydroxide in 1 cm<3> of water. The reaction mixture is boiled

about 2 hours with a reflux condenser under nitrogen. After cooling, 0.6 cm3 of glacial acetic acid is added, the mixture is evaporated in vacuo to dryness, the residue is treated three times with 10 cm3 of acetone each time and filtered after each treatment. The combined filtrates are evaporated under reduced pressure to dryness, and the reserver acid N-oxide thus obtained is recrystallized from methanol. Temp. 240—242° (decomposition).

Example 8:

To a suspension of 0.46 g of reser acid N-oxide in 15 cm 3 of methanol, which is heated to partial dissolution and then cooled in an ice bath, is added 120 cm<3> of an ethereal solution of diazomethane (prepared from 3.3 g of nitrosomethyl -urea). The reaction mixture is allowed to stand for several hours with partial shaking in an ice bath, then at ice bath temperature for a further 1 hour and at room temperature for approximately 16 hours, the solution is evaporated under normal pressure to 30 cm<3> and evaporated to dryness in vacuum. Thus, crude methyl-reserpate-N-oxide is obtained.

0.1 g of this is dissolved in 1 cm3 of methanol and 0.1 cm<3> of 17% nitric acid is added. The formed methyl-reserpate-N-oxide-nitrate is filtered off and recrystallized from methanol. It melts at 250-253° during decomposition.

In the same way, starting from other diazoalkanes such as diazoethane or diazopropane, the corresponding ethyl-respectively propyl-reserpate-N-oxides are obtained. If, instead of starting from reserpic acid N-oxide, one starts from deserpidic acid N-oxide, the corresponding alkyl deserpidate N-oxides are obtained.

Example 9:

0.19 g of reserpine N-oxide is added a

solution of 0.02 g of sodium in 10 cm3 of methanol, and the mixture is refluxed for half an hour, cooled and diluted with 10 cm<3> of water. The mixture is made strongly acidic by careful addition of concentrated hydrochloric acid, extracted with 20 ems ether and then two more times with 10 cm:> ether each time. The extracts are washed separately with the same 2 portions of 5 cm<3> of a 5% sodium chloride solution. Both sodium chloride solutions are added to the aqueous phase obtained by extraction, the resulting solution is made basic with concentrated aqueous ammonia and extracted three times with 10 ems methylene chloride each time. The combined extracts are dried over anhydrous potassium carbonate and evaporated in vacuo. The residue is dissolved in ethyl acetate, filtered from any insoluble particles, the solution is evaporated in vacuo and the solid residue is redissolved in 1 ml of methanol. To this solution is added 0.1 cm<3> of 17% nitric acid, and after filtering off the formed crystals, methyl-reserpate-N-oxide-nitrate is obtained, which after recrystallization from methanol melts at 249-251° during decomposition.

In the same way, starting from sodium ethanolate, ethyl reserpate N-oxide is obtained.

Example 10:

0.411 g of methyl reserpate is treated with

2.06 cm<3> of a 0.962-n. solution of perbenzoic acid in methylene chloride. It is allowed to stand for 15 minutes in an ice bath, then evaporated to dryness and the residue crystallized from methanol. Thus, methyl-reserpate-N-oxide-

benzoate with m.p. 160° (decomposition).

In the same way, methyl deserpidate or deserpidic acid allows itself to be oxidized to methyl deserpidate N-oxide and deserpidic acid N-oxide, respectively.

If reseric acid is treated in an analogous way, reseric acid-N-oxide-benzoate with m.p. 222—225° (decomposition).

Example 11: Reserpine N-oxide can be transferred to its salts in the following way.

A solution of reserpine N-oxide in ethanol is added to a slight excess of perchloric acid, whereby reserpine N-oxide perchlorate with m.p. 240—242° (decomp.) crystallizes out.

A solution of reserpine N-oxide in methanol is added to a slight excess of dilute hydrochloric acid, the formed salt is filtered off and crystallized by dissolving in a mixture of hot methylene chloride and methanol and distilling off the methylene chloride. One thus obtains reserpine-N-oxide-hydrb-chloride with m.p. 235—238° (decomposition).

In an analogous way, reserpine-N-oxide-sulphate is obtained, m.p. 236—237° (decomposition),

reserpine N-nitrate, m.p. 242—250° (decomposition) and reserpine N-oxide-oxalate, m.p. 210—212° (decomposition).

Example 12: '•

0.321 g of 3-epi-α-yohimbine (alkaloid 3078), dissolve in 30 cm3 of methylene chloride and

treated at 0° with 2.92 cm<3> of a 0.61-n.

solution of benzoic acid in chloroform. After standing for 15 minutes, the reaction mixture is evaporated to dryness and recrystallized from methanol-water. The 3-epi-α-yohimbine-N-oxide-benzoate thus obtained sinters at 149° and melts at 160°.

Alkaloid 3078, which is used as starting material, can e.g. obtained as follows: 40 kg of a finely powdered root material of Rauwolfia serpentina is percolated

Benth. so long, until you no longer get

some positive alkaloid reaction with Mayers

reagent. The methanol extract is evaporated in

vacuum to dryness, diatomaceous earth is added, and the residue is processed three times with

a total of 20 1 water. Then add 20 1

ether, containing 10% methanol, adjust the pH by adding aqueous ammonia to 7, stir for 10 minutes and separate from

the organic layer. The aqueous solution

is covered again with 20 L of ether, which contains 10% methanol, and the pH is brought to 9.2. After

Stirring for 10 minutes separates from the aqueous layer, clears the organic layer by filtration and stirs for 30 seconds at 350 cm<3>

2-n. hydrochloric acid. The aqueous layer is quickly separated and the organic is extracted 4 times with 150 cm3 2-n. hydrochloric acid, stirring each time for 2 minutes. Both of the first acid extracts are combined to extract I and the last three to extract II. After standing for three hours at 5°, 35 g of extract I and 3.5 g of a crystalline substance are obtained from extract II. A further amount of 20 g of crystalline substance is obtained from the filtrates after 18 hours. The mother liquors are combined, and the basic liquors

parts are precipitated by the addition of an over-

shot of aqueous ammonia. The mixture is thoroughly stirred for a few hours and left to stand

overnight at 5°, whereby the rubber

like precipitate is converted into a granular form. One can distinguish from the slightly brown bottom

fall by filtration, wash it with water and dry in vacuum at 40°. 7 g of this residue is dissolved in 50 cm<3> benzol, and absorbed by 200 g of medium-active aluminum oxide which is washed with acid, and from the column elu-

are with benzol, then with benzol containing acetone in increasing amounts and finally with portions of every 50 cm<3> meta-

nil Alkaloid 3078 is obtained from the first three methanol extracts, which are combined and evaporated to dryness. It can be recrystallized from methanol-water (1:1) and melts at 124-128°, |>] ^ = -96° (in pyridine).

Claims (3)

1. Process for the production of new organic N-oxides with the partial structure one - ■ i characterized by treating compounds containing, the nucleus with the formula: which in positions 3, 15, and 20 have the stereochemical configuration of reserpine and contain at least one substituent in ring E, with N-poxidizing agents, and, if desired, treating obtained compounds with esterified hydroxyl and/or carboxyl groups in ring E with alkaline saponifiers funds, and/or sells the obtained connections parts with free hydroxyl and/or carboxyl groups in ring E with esterifying agents, and/or converts obtained salts into the free compounds or free compounds into their salts. 2. Method according to claim 1, characterized in that compounds with the formula are used as starting materials: wherein R is hydrogen or a methoxy group, R 2 is a hydroxyl group and a free or esterified carboxyl group, or wherein R 2 is an esterified hydroxyl group and R is an esterified carboxyl group. 3. Procedure according to the claims 1-2, characterized in that peracids, preferably organic peracids, e.g. perbenzoic acid.